The composition and volume of the body fluid are determined by the kidney. Thus, the mechanisms through which the kidney senses, responds to and adjusts the composition of the forming urine constitute the principal pathways through which the body controls its internal environment. The central importance of these mechanisms in human health is aptly illustrated by the pathophysiological consequences of their perturbation. Breakdowns in the regulation of renal fluid and electrolyte transport result in a wide variety of serious and common conditions. In order to understand how the composition of the urine, and thus of the body fluid is determined, it is necessary to develop a holistic understanding of all of these processes. It is critical to identify the cellular and molecular mechanisms through which the properties of transport proteins and of the paracellular pathway are determined. In addition, it is necessary to elucidate the cellular machinery that controls these regulatory processes. As has been true for our entire history, the overall goal of this Program Project is to understand the mechanisms underlying renal fluid, electrolyte and macromolecule transport. Towards this end, we use a broad spectrum of techniques to address a continuum of problems ranging from the molecular characterization of individual transport-related proteins to the contribution of these proteins to integrated renal function at the level of single cells, intact tubules, the kidney, andthe whole animal. The specific objectives of these projects together constitute a collaborative and synergistic effort to define the mechanisms that regulate multiple aspects of renal transport. No segment of the renal tubule and none of the transport processes that it mediates work in isolation. By exploring several transport processes simultaneously and through a variety of collaborative approaches, we will be able to generate new insights into these complex inter-relationships. It is only through such a coordinated effort that a systematic understanding of renal function can be generated.